9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl] methoxyl]propyl]adenine fumarate (1) has the following structure:

9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl] methoxyl]propyl]adenine fumarate (I) is a nucleoside reverse transcriptase inhibitor and a prodrug of tenofovir (PMPA). PMPA is similar to the natural nucleoside monophosphate in structure and is rapidly transformed into the active metabolite PMPA diphosphate (PMPApp) in the body. PMPApp competes with natural 5′ deoxyadenosine triphosphate and is incorporated into the DNA strand of viruses. However PMPApp cannot perform a 5′, 3′-phosphodiester bond coupling reaction due to the lack of a 3′ OH group, such that DNA strand extension is blocked and replication of the virus is ultimately blocked (FIG. 1). It has been proven that PMPA has anti-human immunodeficiency virus (HIV) activity and anti-hepatitis B virus (HBV) activity.
However, PMPA contains a phosphate group, which is usually negatively charged at physiological pH and the polarity of it is too strong to pass through biological membranes, which leads to poor oral bioavailability, a low tissue distribution coefficient, and a certain nephrotoxicity. Therefore, in the development of such drugs, it is necessary to use the principle of pro-drugs to mask the negative charge of phosphate groups in order to eliminate the drawback of such drugs. A diester prodrug of PMPA, tenofovir disoproxilfumarate (TDF), developed by Gilead company was approved by the U.S. Food and Drug Administration (FDA) in 2001 for the treatment of HIV infection.
TDF has significantly improved the pharmacokinetic properties of PMPA to some extent, but it is rapidly hydrolyzed in the body by non-specific esterases that are widely present in plasma, particularly in the presence of carbonate esterases in intestinal epithelial cells, to release PMPA. High concentrations of PMPA in the plasma are quickly excreted out of the body due to its poor membrane permeability, which leads to difficulty in maintaining adequate concentration at the infected site. In addition, PMPA is the substrate of an organic anion transporter (hOAT) in renal proximal tubule epithelial cells, and the high concentration of PMPA in the plasma easily accumulates in renal proximal tubular epithelial cells, which results in a certain risk of renal toxicity.
A new generation of monophosphonamidate monoester prodrug overcomes the above-mentioned shortcomings of TDF which is very stable in plasma and is not easily hydrolyzed by esterases. When it is absorbed into the cells, it is immediately transformed into PMPA in the presence of serine proteases (cathepsinA) and specific amidases. Therefore, it has a better tissue permeability and lymphoid tissue and cell targeting. The monophosphonamidate monoester prodrug GS7340 (refer to PCT patent application WO2013052094 A2) developed by Gilead company has successfully entered into phase III clinical trials, and the results show that GS7340 has a stronger anti-virus capability and better safety in comparison to 30 times the dose of TDF.
9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate (1), like GS7340, can release the active ingredient PMPA in cells. Its auxiliary group is cleverly designed, with its structure being different from GS7340 in only a single methyl group, and the removing mechanism and manner of the auxiliary group in cells is also almost the same as those of GS7340. It can be expected that HS-10234, due to its advantages in absorption and distribution, will be more effective than TDF and other prodrugs in improving the efficacy of the active ingredient PMPA. As the most promising new generation of PMPA prodrugs, HS-10234 will benefit the majority of patients.
It is known to the person skilled in the art that the polymorphic form of a drug has become an essential pan of the pharmaceutical research process and the quality control and detection of the finished drug product. The study of drug polymorphism is beneficial to selecting the bioactivity of a new drug compound, to improving the bioavailability, to improving the clinical curative effect, to selecting and designing the drug administration route, and to determining the parameters of the pharmaceutical preparation process, thereby improving the quality of drug production. The bioavailability may be significantly different among different crystal forms for the same drug. For one drug, some crystal forms may have higher biological activity than other crystal forms. To provide a crystal form of tenofovir prodrug with higher bioactivity and more suitable medical application is a technical problem that the medical field has been looking forward to solving.